Perindopril(I), (2S)-2-[(1S)-1-carbethoxybutylamino]-1-oxopropyl-(2S,3aS,7aS)-perhydroindole-2-carboxylic acid of formula (I), known generically as perindopril, represented by the formula (I) is a valuable angiotensin-converting enzyme (ACE) inhibitor, a family of drugs used to treat high blood pressure and some types of heart failure.

Perindopril(I) is marketed under the brandname ACEON®. It is commercially sold as the erbumine salt (II) and was launched in France in 1987; Germany in 1989; Belgium, Denmark, Ireland, Netherlands, and the UK in 1990; and in Italy in 1992 for the treatment of hypertension. This drug, which is an invention of M/S Adir et Compagnie, France is marketed by M/S Solvay Pharmaceuticals in the USA.
Perindopril is disclosed in EP 0049658 for the first time, however the synthetic procedure for preparation of perindopril was not exemplified.
European patent EP 0308341 discloses process for preparation of perindopril. According to this process the compound of the Formula V is reacted with the compound of the Formula II in the presence of dicyclohexyl carbodiimide and 1-hydroxy-benzotriazole, whereafter the benzyl ester of is debenzylated to give perindopril of the Formula I, which is then converted into the salt by reacting with t-butylamine.

The drawback of this process is that the purity of the perindopril thus obtained is not satisfactory and for this reason a series of purification steps is required to provide a product which meets the severe quality requirements of pharmaceutical active ingredients. The reason of said disadvantage is that the coupling reaction of the compounds of the Formulae V and II is carried out in the presence of dicyclohexyl carbodiimide which results in the formation of a considerable amount of contaminations of the benzyl esters of the Formulae VII and VIII which are transformed by debenzylation into the compounds of the Formulae VII′ and VIII′. The removal of said contaminations is cumbersome.


Our copending application WO 2004/075889 teaches process for the preparation of Perindopril and salts thereof.
The process described therein comprises reaction of compound of formula A,
wherein X is chlorine or bromine with compound of formula B followed by catalytic hydrogenation to give the perindopril of formula I. Converting Perindopril to tert-butyl amine salt.

The Perindopril obtained from the above process contains 0.16% pharmacopoeial impurity-I (diastrereomeric impurity) of unknown nature.
Surprisingly the present inventors have found that Perindopril thus obtained when converted to dicyclohexylamine salts and then converted to its tert-butyl amine salts, all the unknown impurity found above in removed and the resulting Perindopril is more than 99.9% pure